Current nutritional strategies for very preterm infant in this country are resulting in postnatal growth failure from which the neonate does not recover by the time of hospital discharge. Undernutrition, particularly insufficient protein intake during critical development periods adversely affects long-term neurodevelopmental and health outcomes. Efforts to optimize nutritional support, therefore, particularly in the first weeks of life, are critical to reversing nutritionally related adverse outcomes in this vulnerable population. The overarching hypothesis of this proposal is that there are a variety of nutritional and metabolic strategies for different types of infants and different types of postnatal conditions and disease states that will optimize anabolism, reduce morbidity and maximize growth in very preterm and critically ill neonates. The fundamental research goal of this proposal is to determine optimal early nutritional management approaches that will maximize protein accretion in extremely premature neonates. Specific Aim 1 will test the hypothesis that relatively high amino acid intake initiated in the immediate neonatal period and sustained at fetal delivery rates through close monitoring of nutrient intake will result in improved growth outcomes compared when compared to both historical controls that are not monitored. Specific Aim 2 will determine the energy intake that will optimize protein accretion at any given amino acid intake. Specific Aim 3 will address the metabolic effects of exogenous insulin administration in early neonatal hyperglycemia on protein accretion and lactate production. Specific Aim 4 will develop methodology to increase acceptability of protein metabolism studies in vulnerable neonatal populations. This work proposed in this award builds on the candidate's past landmark research in improving early neonatal nutrition. The candidate has developed a unique set of research experiences and skills that will allow for successful conduct of complex nutritional investigations in unstable preterm neonates. The candidate has an extensive record of both funding in clinical investigation and mentoring trainee physicians in patient-oriented research. A mid-career clinical investigator award would expand the time the candidate has for patient-oriented research on determining safe and efficacious anabolism-promoting strategies in very preterm and critically ill neonates during the immediate postnatal course, allow for training of young investigators who wish to pursue independent research careers in neonatal nutrition and metabolism, and advance the candidate's career goals of optimizing nutrition and metabolism in this vulnerable population of infants.